Processes for the preparation of 4-alkoxy-3-hydroxypicolinic acids

ABSTRACT

4-Alkoxy-3-hydroxypicolinic acids may be conveniently prepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series of chemical steps selected from bromo substitution, nitrile hydrolysis and halogen reduction that are conducted as a single pot process. 4,6-Dibromo-3-hydroxypicolinonitrile may be prepared from furfural in a series of chemical steps selected from cyano-amination, amine salt formation and bromination-rearrangement.

FIELD

The present disclosure concerns processes for the preparation of4-alkoxy-3-hydroxypicolinic acids. More particularly, the presentdisclosure concerns a process for the preparation of4-alkoxy-3-hydroxypicolinic acids from furfural.

BACKGROUND

U.S. Pat. No. 6,521,622 B1 and U.S. application Ser. No. 61/747,723describe inter alia certain heterocyclic aromatic amide compounds ofgeneral Formula

and their use as fungicides.

These disclosures also describe the preparation of4-alkoxy-3-hydroxypicolinic acids and derivatives thereof as keyintermediates in the preparation of these heterocyclic aromatic amidecompounds. It would be useful to have an efficient and scalable processroute to 4-alkoxy-3-hydroxypicolinic acids from inexpensive rawmaterials.

SUMMARY

The present disclosure concerns processes for the preparation of4-alkoxy-3-hydroxypicolinic acids of Formula A

wherein R¹ is a C₁-C₃ alkyl;from the compound of Formula B

The compound of Formula A may be prepared in a one-pot process thatcomprises the following steps:

a) creating a first mixture containing an alkali metal alkoxide ofFormula C

MOR¹   C

-   -   wherein M is Na or K, and R¹ is a C₁-C₃ alkyl;        and the compound of Formula B and heating the first mixture;

b) creating a second mixture by adding water, a strong base, and zincmetal to the first mixture;

c) heating the second mixture; and

d) isolating the compound of Formula A.

The present disclosure also concerns a process for the preparation ofthe compound of

Formula B

from the compound of Formula D

The compound of Formula B may be prepared in a process that comprisesthe following steps:

a) creating a first mixture by combining together a 2-phasewater-organic solvent system, an ammonia source, a cyanide source andthe compound of Formula D;

b) separating a second mixture from the first mixture containing thecompound of Formula E as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture;

-   -   wherein the mineral acid is HCl, HBr, H₂SO₄, HNO₃ or H₃PO₄;

d) separating a fourth mixture from the third mixture that is an aqueousmixture containing the compound of formula F;

-   -   wherein X is Cl, Br, HSO₄, NO₃ or H₂PO₄;

e) adding a brominating agent, selected from the group including:

-   -   i) bromine and a bromide compound with an oxidant; and    -   ii) a bromide compound with an oxidant,        to the fourth mixture to form a fifth mixture; and

f) isolating the compound of Formula B from the fifth mixture.

The present disclosure also concerns a process for the preparation ofthe compound of Formula G

from the compound of Formula D

The compound of Formula G may be prepared in a process that comprisesthe following steps:

a) creating a first mixture by combining together water, an organicsolvent, an ammonia source, a cyanide source and the compound of FormulaD;

b) separating a second mixture from the first mixture containing thecompound of Formula E as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture;

-   -   wherein the mineral acid is HCl, HBr, H₂SO₄, HNO₃ or H₃PO₄;

d) separating a fourth mixture from the third mixture that is an aqueousmixture containing the compound of formula F;

-   -   wherein X is Cl, Br, HSO₄, NO₃ or H₂PO₄;

e) adding a brominating agent that is a bromide compound with an oxidantto the fourth mixture to form a fifth mixture; and

f) isolating the compound of Formula G from the fifth mixture.

DETAILED DESCRIPTION

The terms “isolate,” “isolating,” or “isolation” as used herein mean topartially or completely remove or separate the desired product from theother components of a finished chemical process mixture using standardmethods such as, but not limited to, filtration, extraction,distillation, crystallization, centrifugation, trituration,liquid-liquid phase separation or other methods known to those ofordinary skill in the art. The isolated product may have a purity thatranges from <50% to >50%, and may be purified to a higher purity levelusing standard purification methods. The isolated product may also beused in a subsequent process step with or without purification.

In the process described herein 4-alkoxy-3-hydroxypicolinic acids areprepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series ofchemical steps involving bromo substitution, nitrile hydrolysis, andhalogen reduction. The current disclosure describes an improved processfor the preparation of 4-alkoxy-3-hydroxypicolinic acids from4,6-dibromo-3-hydroxypicolinonitrile utilizing a more efficient“one-pot” process.

Also described herein are improved processes for the preparation of4,6-dibromo-3-hydroxypicolinonitrile from furfural. The processesutilize partial or complete replacement of bromine with abromide/oxidant pair of reagents that produce bromine in situ. Such aprocess improvement decreases the need to handle elemental bromine andimproves the efficiency of bromine atom utilization.

The in situ generation of bromine in the preparation of4,6-dibromo-3-hydroxypicolinonitrile from furfural described herein isequivalent to using elemental bromine and surprisingly, the presence ofthe oxidant does not negatively impact the Strecker or rearrangementreactions. In addition, it was also surprising that the oxidant did notlead to degradation or oxidation of the pyridine ring or the nitrilegroup of the 4,6-dibromo-3-hydroxypicolinonitrile.

A. Preparation of Compound of Formula A

An improved process for the preparation of 4-alkoxy-3-hydroxypicolinicacids of Formula A from 4,6-dibromo-3-hydroxypicolinonitrile (compoundB) utilizing a more efficient “one-pot” process is described. Theprocess involves treating the compound of Formula B first with a sodiumalkoxide, and then with zinc metal, aqueous strong base, and optionally,adding additional aqueous strong base, and finally acidifying the finalreaction mixture with aqueous strong acid to produce the compound ofFormula A (wherein R¹ is a C₁-C₃ alkyl).

In one embodiment of this process, the reaction of the compound ofFormula B with sodium methoxide can be conducted in a dipolar, aproticsolvent such as DMSO or sulfolane, optionally with added methanol, or inmethanol as the solvent. Utilizing at least 2 molar equivalents ofsodium methoxide, preferably 2.5-3 molar equivalents, and heating atfrom about 50 to about 80° C. for about 1 hour to about 24 hours thedisplacement of the 4-bromo group with methoxide is complete. Theresulting reaction mixture can then be diluted

with water and a strong, aqueous base, such as potassium hydroxide orsodium hydroxide (2-3 molar equivalents), treated with from about 1 toabout 3 molar equivalents of zinc metal (i.e., Zn dust with a particlesize of <10 μm, Zn powder with a particle size of <150 ∥m, or anotherhigh surface area Zn solid) and stirred at from about 20° C. to about70° C. until reduction of the 6-bromo group is complete. Additionalstrong aqueous base (2-3 molar equivalents) can then be added and theresulting mixture heated at from about 80° C. to about 95° C. for fromabout 4 to about 24 hours. The desired compound of Formula A (wherein R¹is methyl) may be isolated by acidifying the reaction mixture andemploying standard isolation and purification techniques.

In another embodiment of this process, after the reaction of thecompound of Formula B with sodium methoxide is complete, the resultingreaction mixture can then be diluted with water, a strong aqueous base(4-6 molar equivalents), and zinc metal, and then maintained attemperatures ranging from about 20° C. to about 95° C. for from about 2to about 48 hours. Following completion of the zinc reduction and basehydrolysis reactions, the desired product can be isolated by acidifyingthe reaction mixture and employing standard isolation and purificationtechniques.

In another embodiment of this process, after the reaction of thecompound of Formula B with sodium methoxide is complete, the resultingreaction mixture can then be diluted with water and strong aqueous base(4-6 molar equivalents), and the resulting mixture heated at from about80° C. to about 95° C. for from about 4 to about 24 hours to completehydrolysis of the nitrile group. The resulting mixture can then betreated with zinc metal and then maintained at temperatures ranging fromabout 20° C. to about 70° C. until reduction of the 6-bromo group iscomplete. Following completion of the zinc reduction and base hydrolysisreactions, the desired product can be isolated by acidifying thereaction mixture and employing standard isolation and purificationtechniques.

In another embodiment of this process, after the reaction of thecompound of Formula B with sodium methoxide is complete, the hydrolysisof the nitrile group and the reduction of the 6-bromo group may becarried out concurrently by adding the water, the strong aqueous base,and the zinc metal (in one portion or by addition over a period of time)to the reaction vessel and heating it from about 80° C. to about 95° C.for the time needed to complete the hydrolysis of the nitrile group andthe reduction of the 6-bromo group.

B. Preparation of Compound of Formula B

As shown in Scheme II, furfural (Formula D) can be converted in aprocess using chemical steps a, b and c into4,6-dibromo-3-hydroxypicolinonitrile (Formula B). The

cyano(furan-2-yl)methanaminium halide salt of Formula F is prepared in abiphasic process (organic-aqueous, 2-phase solvent system) by firstreacting furfural (Formula D) with at least one equivalent each of anammonia source and a cyanide source (Step a) in a reaction

known in the art as the Strecker synthesis of α-aminonitriles, which isdescribed in Organic Syntheses, Coll. Vol. I, page 21 and Coll. Vol.III, pages 84 and 88, to provide the amino(furan-2-yl)acetonitrile ofFormula E. Suitable ammonia sources include: ammonium salts such as, butnot limited to, ammonium acetate, ammonium bromide, ammonium chloride,ammonium formate, ammonium sulfate and ammonium cyanide; ammoniadissolved in an organic solvent such as, for example, ammonia inmethanol, ammonia in ethanol and ammonia in dioxane; ammonia in water(i.e., ammonium hydroxide); and liquid, anhydrous ammonia or gaseousammonia. Suitable cyanide sources include: cyanide salts such as, butnot limited to, sodium cyanide, potassium cyanide and ammonium cyanide;and hydrogen cyanide which may be added in a continuous-addition mannerwith ammonia to the furfural. The reaction (Step a) is carried out in a2-phase solvent system consisting of water and a water immisciblesolvent selected from: ethers, such as diethyl ether, methyl t-butylether (MTBE), tetrahydrofuran (THF), and 2-methyltetrahydrofuran(2-MeTHF); esters, such as ethyl acetate, and isopropyl acetate;alkanes, such as hexane, cyclohexane, heptane, and octane; aromatics,such as anisole, toluene and a xylene or a mixture of xylenes, andmixtures thereof. Such a reaction has been described in WO Application2000049008, page 55. The present reaction is typically conducted withagitation sufficient to maintain an essentially uniform mixture of thereactants. Such a reaction may be conducted for about 1 to about 50hours at between about 15° C. and about 30° C.

After the reaction to prepare the amino(furan-2-yl)acetonitrile ofFormula E is complete, the organic phase of the 2-phase solvent systemcontaining the compound of Formula E is easily separated from theaqueous phase by standard phase separation and extraction methods. Thecompound of Formula E, as a solution in the organic phase, is thenconverted into the salt of Formula F by treatment with an aqueoussolution of a mineral acid. Suitable mineral acids include, but are notlimited to, hydrobromic acid (HBr), hydrochloric acid (HCl), nitric acid(HNO₃), sulfuric acid (H₂SO₄), and phosphoric acid (H₃PO₄). The presentreaction may be conducted at from about 0° C. to about 25° C. Aftersuitable mixing of the organic phase containing the compound of FormulaE and the aqueous solution of the mineral acid, the aqueous acidsolution containing the cyano(furan-2-yl)methanaminium halide salt ofFormula F is separated from the organic phase by standard phaseseparation and extraction methods and is ready for the finalbromination/rearrangement reaction (Scheme II, Step c) to prepare thecompound of Formula B.

In the bromination/rearrangement reaction step of the process, thecyano(furan-2-yl)methanaminium salt of Formula F is treated with abrominating agent, such as bromine, to provide the product of Formula B.The starting material of Formula F, wherein X is Br, Cl,

NO₃, HSO₄, or H₂PO₄, may be treated with a suitable brominating agent.From about 3 to about 6 molar equivalents of bromine may be used. Thereaction is preferably conducted using about 3-5 molar equivalents ofbromine and the bromide salt of the compound of Formula F (X═Br). It isoften convenient to use an excess of the brominating agent such as a 5%,10% or 15% molar excess, to insure the reaction proceeds to completion.The reaction is preferably carried out in a protic solvent or reactionmedium such as water, or mixtures of water and a water soluble, organicsolvent such as, for example, methanol, ethanol, tetrahydrofuran,dioxane or acetonitrile. The temperature at which the reaction isconducted is generally between about 10° C. and about 25° C. Uponcompletion of the addition of the bromine, the reaction mixture may beallowed to warm slowly to room temperature and stir for 10-48 hours orthe reaction may be heated at about 30-40° C. to complete the reaction.Optionally, the reaction time may be shortened by adding a base, suchas, for example, 2-4 molar equivalents of sodium acetate, to thereaction. After the reaction is complete the desired product isrecovered by employing standard isolation and purification techniques.

In some embodiments of the present disclosure, bromination/rearrangementof the compound of Formula F may involve the use of one or morebrominating agents selected from: (1) bromine, and (2) a bromidecompound paired with an oxidant. It is known in the literature thatbromide compounds such as, for example, HBr, KBr, and NaBr, whencombined with an oxidant such as, for example, hydrogen peroxide,potassium peroxymonosulfate (i.e., Oxone®), DMSO or t-butylhydroperoxide, under appropriate reaction conditions, can producebromine (this is referred to herein as in situ generation of bromine).Use of a bromide compound that is a salt such as, for example, NaBr orKBr, for the in situ generation of bromine, also requires the use of anacid for bromine formation). The acid may be selected from the groupincluding HBr, HCl, H₂SO₄, HNO₃, H₃PO₄, acetic acid and mixturesthereof. Such an approach that involves the in situ generation ofbromine offers the advantage of: limiting or eliminating the use ofelemental bromine, improving the bromine atom efficiency of the process,and reducing the formation and disposal of bromide waste streams.

In some embodiments of the present disclosure, use of a bromide compoundsuch as, for example, HBr, KBr, or NaBr paired with an oxidant such ashydrogen peroxide in the process to prepare the compound of Formula Bfrom the compound of Formula F (X═Br) can be conducted by slowly addingthe hydrogen peroxide (the oxidant) to the compound of Formula F and thebromide compound (i.e., KBr or NaBr as the bromide compound whichrequires the use of an acid for in situ bromine formation) at ambienttemperature and maintaining the temperature at less than about 50° C.during the addition. From about 3-5 molar equivalents of hydrogenperoxide relative to the compound of Formula B may be used in thepresence of a sufficient amount of the bromide compound (2-5 molarequivalents) and an acid in the process.

Chemical literature describing the use of bromide compounds withoxidants to conduct bromination chemistry include: a) “Simple andPractical Halogenation of Arenes, Alkenes, and Alkynes with HydrohalicAcid/H2O2 (or TBHP),” Tetrahedron, 55, (1999) 1127-1142, b) “OxidativeHalogenation with “Green” Oxidants: Oxygen and Hydrogen Peroxide,”Angew. Chem. Int. Ed., 2009, 48, 8424, and references therein. Patentsdescribing the generation of bromine from the reaction of bromide saltsor HBr with hydrogen peroxide include U.S. Pat. Nos. 5,266,295,4,029,732 and 2,772,302.

C. Preparation of Compound of Formula G

Another embodiment of the present disclosure involves a process for thepreparation of the compound of Formula G from furfural. In the firstpart of this process, furfural is converted into thecyano(furan-2-yl)methanaminium bromide salt of Formula F (X is Br),using the biphasic process as described herein. In the next step of theprocess, the bromide salt of Formula F is combined with additionalaqueous HBr (1.5 equivalents) and then reacted with from about 3 toabout 4 molar equivalents of hydrogen peroxide (relative to the bromidesalt of Formula F) to provide 3-hydroxy-picolinonitrile (Formula G). Thetemperature at

which the hydrogen peroxide addition may be conducted is between about0° C. and about 50° C. Upon completion of the addition of the hydrogenperoxide, the reaction mixture is allowed to stir at room temperaturefor about one to about 24 hours. After the reaction is complete, thedesired product is recovered by employing standard isolation andpurification techniques.

D. Preparation of Compound of Formula H

The conversion of the 4-alkoxy-3-hydroxypicolinic acid of Formula A tothe 3-acetoxy compound of Formula H, may be accomplished by acetylatingthe compound of Formula A with one or more acetylation reagents selectedfrom acetic anhydride and acetyl chloride, bases selected from pyridine,alkyl substituted pyridines, and trialkylamines, or utilization ofSchotten-Baumann reaction conditions.

The product obtained by any of these processes, can be recovered byconventional means, such as evaporation, filtration or extraction, andcan be purified by standard procedures, such as by recrystallization orchromatography.

The following examples are presented to illustrate the disclosure.

EXAMPLES Example 1a. 3-Hydroxy-4-methoxypicolinic acid

A slurry of sodium methoxide (25 g, 0.45 mol) was prepared with 50 mL ofanhydrous DMSO and 1 mL of MeOH. To this slurry was added a solution of4,6-dibromo-3-hydroxy-2-picolinonitrile (50 grams, 0.181 mol) and about50 mL of anhydrous DMSO, which was added over 30 minutes. The reactionwas maintained between 50-65° C. during the addition. After the additionwas complete, the reaction was allowed to stir for an additional hourat >50° C. The reaction was determined to be complete by ¹H NMRanalysis. The reaction was allowed to cool to 35° C., and then 100 mL ofwater, followed by 45% KOH (40 mL, 468 mmol) were added to the reactionsolution. Zinc dust (15.4 g 234 mmol; <10 micron particle size) was thenadded in 5 gram portions at 15 min intervals, which led to a temp riseto about 45° C. The reaction was allowed to stir overnight at ambienttemperature. The reaction was not complete, so the reaction was heatedto 50° C., and then additional Zn dust (4.8 grams, 74 mmol) was added.The reaction was complete after 3 hours. Additional KOH (45% aqueous, 40mL, 468 mmol) was added to the reaction mixture. The reaction was thenheated at 94° C. for 12 hours to complete the hydrolysis. The reactionwas cooled to ambient, and then filtered to remove solids. The solidswere washed with about 100 mL of water into the reaction solution. ThepH of the combined filtrate and wash solution was then adjusted to 0.4with 12N HCl. The resulting mixture was allowed to stir for about 1 hourto ensure the pH was stable, and then the solids were collected byfiltration. The resulting off-white solids were washed with acetone. Thematerial was dried in a vacuum oven at 50° C. to afford4-methoxy-3-hydroxypicolinic acid as a very pale yellow powder (19.22 g,63.2% yield with 96% purity, which equates to 60.7% yield). The organicpurity was 99.75% as determined by HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ8.03 (d, J=6.4 Hz, 1H), 7.39 (d, J =6.4 Hz, 1H), 4.04 (s, 3H).

Example 1b. 3 -Hydroxy-4-methoxypicolinic acid

Neat sodium methoxide (14.7 g, 271 mmol) was added to a solution of4,6-dibromo-3-hydroxypicolinonitrile (30.2 g, 109 mmol) and sulfolane(120 g) over a 30 minute period, which led to a temperature rise to 50°C. The reaction was then heated at 60° C. for 18 hours.

The reaction solution was allowed to cool to ambient temperatures, andthen 150 mL of DI water was added to the reaction, followed by 50 mL of45 wt % KOH (5.4 equiv, 586 mmol). Zn dust (113 mmol, 7.5grams) wasadded, and then the reaction was heated to 40° C. After 2 hours,additional Zn dust (2.5 grams, 38 mmol) was added, and then the reactionwas heated to 60° C. for an additional 2 hours. The reaction was allowedto stir overnight at ambient. ¹H NMR analysis of the reaction mixtureindicated that the debromination was complete. The reaction was filteredto remove solids, 45% KOH (50 mL, 596 mmol) was added to the filtrate,and then the resulting solution was heated to about 90° C. The reactionwas allowed to stir at about 90° C. for 5.5 h, which resulted in nearcomplete conversion. The reaction was allowed to stir at about 90° C.overnight. The reaction mixture was cooled to <30° C., and then the pHwas adjusted to 0.8 with 40% sulfuric acid, which led to the formationof solids. The solids were isolated by filtration and then dried toyield a solid, which was greater than a 100% yield. The material wasslurried overnight in 0.5 pH hydrochloric acid. The material was thenisolated by filtration and drying to afford 10.3 grams of4-methoxy-3-hydroxypicolinic acid as an off-white powder, which wasdetermined to be 94% pure by HPLC (53% yield).

Example 1c. 3-Hydroxy-4-methoxypicolinic acid

A 500 mL 3-neck flask was charged with sodium methoxide (25 g, 0.462mol) and 25 mL of dimethyl sulfoxide. The sodium methoxide/DMSO mixturewas placed under inert gas and mechanically stirring to create a freeflowing slurry. A solution of 4,6-dibromo-3-hydroxypicolinonitrile (50.3grams, 0.181 mol, DBHP, 96.2 wt % purity) in about 25 mL of anhydrousDMSO was prepared in a separate vessel. The DBHP solution was added tothe sodium methoxide/DMSO mixture over 50 minutes via a syringe pump.The temperature was maintained below 60° C. during the addition. Afterthe addition was complete, the reaction was allowed to stir for anadditional hour. During that time the reaction mixture solidified. 100mL of water followed by 50% KOH (50 mL, 941 mmol) were added to thesolidified reaction mixture. The resulting mixture was stirred for about1.5 hours to break up the solids into a thick slurry. Zn dust (14.8 g,226 mmol) was then added in about 5 gram portions about 20 minutesapart, which led to a temperature rise to about 40° C. Over the courseof the Zn digestion, the reaction thinned into an easily mixed slurry.The reaction was allowed to stir overnight at ambient temperature. Thereaction was then heated up to 95° C. for 24 hours. The reaction wascooled to <20° C., and then the pH of the solution was adjusted to 0.6with aqueous HCl (12 N), which resulted in the precipitation of theproduct. The solids were isolated by filtration, washing with about 50mL of water, and then washed with about 25 mL of acetone. The resultingslightly yellow powder was allowed to dry in the hood, which led to 23.3grams of product. The product was 96% pure as determined by ¹H NMR(versus internal standard), which equated to a 76% yield of the desiredproduct based on the purity of the starting material and finalproduct.¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=6.4 Hz, 1H), 7.39 (d,J=6.4 Hz, 1H), 4.04 (s, 3H).

Example 1d. Cyano(furan-2-yl)methanaminium bromide

To an 500 mL flask outfitted with a stir bar was added 33.65 grams ofammonium acetate (436 mmol), 150 mL of ethyl acetate, 30 mL of DI water,and 10 grams of KCN (154 mmol). Furfural (14 g, 145 mmol) was then addedto the reactor via syringe. The temperature in the reactor increasedfrom about 15° C. to 24° C. The reaction was allowed to stir overnightat ambient. ¹H NMR analysis of the ethyl acetate phase showed that theconversion was >95% complete. 75 mL of 20% aqueous sodium carbonate wasadded to the reactor and allowed to stir for 10 minutes. The sodiumcarbonate solution was removed and then the reaction mixture was washedwith 40 mL of saturated brine. ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (dd,J=2.0, 1.0 Hz, 1H), 6.47 (dd, J=3.4, 1.1 Hz, 1H), 6.42 (dd, J=3.3, 1.7Hz, 1H), 5.08 (s, 1H).

After removal of the brine phase, 24.5 mL of aqueous 48% HBr (1 equiv.,145 mmol) diluted in about 130 ml of DI water was added to the reaction.The reaction was mixed for 15 minutes. The aqueous layer was removed andplaced in a separate vessel. The organic layer was then washed with 2×25mL of DI water. Each wash was added to the holding vessel with theinitial HBr extracted phase. A total of 210.5 grams of aqueous phase wasobtained containing about 14.06 wt % of cyano(furan-2-yl)methanaminiumbromide.

Example 1e. 4,6-Dibromo-3-hydroxypicolinonitrile

52.5 g of the aqueous phase containing 7.38 g (36 mmol) ofcyano(furan-2-yl)methanaminium bromide (14.06 wt % in water) was placedinto a 250 mL flask outfitted with a stir bar. The flask was then placedin an ice bath. After cooling to <10° C., 5.8 g of bromine (36 mmol) wasthen added to the reaction drop wise over 15 minutes resulting in theformation of solids. After stirring for 1 h the reaction was allowed towarm to ambient temperature. Oxone® (27 g, 87.8 mmol) was added to thereaction in portions resulting in the dissolution of the solids and areddish brown liquid phase, which slowly converted to round pellet-likematerial after stirring for 1 h. The reaction was quenched withsaturated, aqueous sodium bisulfite. The solids were then isolated byfiltration, washed with DI water, and then dried overnight to yield 6.25grams of a tan powder. ¹H NMR analysis indicated that the productconsisted of 4,6-dibromo-3-hydroxypicolinonitrile (96.6 mol %, 60.3%yield) and 6-bromo-3-hydroxypicolinonitrile (3.4 mol %, 2.2% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1.00H), 7.75 (d, J=8.9 Hz, 0.034H),7.44 (d, J=8.9 Hz, 0.034H). HRMS (m/z) Positive Ion mode [M+1] calcd forC₆H₃Br₂N₂O 276.8612; found 276.8611.

Example 1f. 4,6-Dibromo-3-hydroxypicolinonitrile

52.5 g of the aqueous phase containing 7.38 g (36 mmol) ofcyano(furan-2-yl)methanaminium bromide (14.06 wt % in water) was placedinto a 250 mL flask outfitted with a stir bar. The flask was then placedin an ice bath. After cooling to <10° C., 5.8 g of bromine (36 mmol) wasthen added to the reaction drop wise over about 15 minutes resulting inthe formation of solids. After stirring for 1 h, 30% hydrogen peroxide(9.4 mL) was added to the reaction via syringe over 20-30 minutes. Thisresulted in the dissolution of the solids and then precipitation of afine powder over a 1-2 hour period. The reaction was quenched withsaturated sodium bisulfite. The solids were then isolated by filtration,washed with DI water, and then dried overnight to yield 6.03 grams of atan powder. ¹H NMR analysis indicated that the product consisted of4,6-dibromo-3-hydroxypicolinonitrile (94.5 mol %, 57.3% yield) and6-bromo-3-hydroxypicolinonitrile (5.5 mol %, 3.2% yield).¹H NMR (400MHz, DMSO-d₆) δ 8.27 (s, 1.00H), 7.75 (d, J=8.9 Hz, 0.075H), 7.44 (d,J=8.9 Hz, 0.075H).¹³C NMR (101 MHz, DMSO-d₆) δ 157.65, 141.95, 135.55,128.76, 124.37, 120.34, 115.97. HRMS (m/z) Positive Ion mode [M+1] calcdfor C₆H₃Br₂N₂O⁺276.8612; found 276.8609.

Example 1g. 3 -Hydroxypicolinonitrile

52.5 g of the aqueous phase containing 7.38 g (36 mmol) ofcyano(furan-2-yl)methanaminium bromide (14.06 wt % in water) was placedinto a 250 mL flask outfitted with a stir bar. 48% HBr (6.2 mL, 55 mmol)was added to the flask with stirring. The flask was then placed in anice bath. After cooling to <5° C., about 7 mL of 30% hydrogen peroxidewas added to the reaction via syringe over 20-30 minutes. This resultedin very little heat evolution. The reaction was allowed to warm toambient temperature, at which point the reaction started to self heat toabout 50° C. The reaction was cooled to 20° C., and then 7 mL of 30%peroxide was added, which resulted in the formation of a precipitate.The reaction was allowed to stir for about 20 min and then the reactionwas quenched with saturated sodium bisulfite, which resulted in atemperature rise to about 40° C. During the temp rise, the solidsdissolved. The reaction was then placed in an ice bath. After stirringfor about 45 minutes, solids developed. The solids were collected byfiltration and washed with DI water. 3-Hydroxypicolinonitrile (1.63grams) was isolated as a tan crystalline solid (37.3% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.19 (dd, J=4.4, 1.3 Hz, 1H), 7.56(dd, J=8.6, 4.4 Hz, 1H), 7.47 (dd, J=8.7, 1.4 Hz, 1H). ¹³C NMR (101 MHz,DMSO-d₆) δ 157.67, 141.93, 135.56, 128.75, 125.99, 124.37, 120.34,115.97. HRMS (m/z) Negative Ion mode [M−1] calcd for C₆H₄N₂O 119.0246;found 119.0240.

Example 1h. 4,6-Dibromo-3-hydroxypicolinonitrile

53 g of the aqueous phase containing 7.45 g (37 mmol) ofcyano(furan-2-yl)methanaminium bromide (14.06 wt % in water) was placedinto a 250 mL flask outfitted with a stir bar. 48% HBr (8.2 mL, 73 mmol)was added to the flask with stirring. The flask was placed in an icebath. After cooling to <5° C., 6 to7 mL of 30% hydrogen peroxide wasadded to the reaction via syringe over 20-30 minutes. This resulted invery little heat evolution. The reaction was allowed to warm to ambienttemperature, at which point the reaction started to self heat to about46-48° C. and became yellow orange in color (homogeneous). The reactionwas cooled to 20° C., and then another 7 mL of the 30% hydrogen peroxidewas added via syringe over 15-20 minutes, which resulted in theformation of a precipitate. The reaction was allowed to stir overnight.The reaction was quenched with sodium bisulfite to yield a slightlyyellow solution with solids. Peroxide test strips indicated no residualperoxides. The solids were collected by filtration, washed with water,and dried to yield 6.22 grams of a light tan powder. ¹H NMR analysisindicated that the product consisted of4,6-dibromo-3-hydroxypicolinonitrile (58.1% yield) and6-bromo-3-hydroxypicolinonitrile (3.8% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 8.27 (s, 1.00H), 7.75 (d, J=8.9 Hz, 0.064H), 7.44 (d, J=8.9 Hz,0.064H).

Example 1i. 4,6-Dibromo-3-hydroxypicolinonitrile

A stock solution of cyano(furan-2-yl)methanaminium chloride was preparedusing 39.21 grams of furfural, 20 grams of sodium cyanide, 96 grams ofammonium acetate in 300 mL of ethyl acetate and 260 mL of water. Afterformation of the a-aminonitrile, 75 mL of saturated sodium carbonate wasadded to the mixture and allowed to mix for 20-30 minutes. The aqueousphase was removed and then the organic phase was subsequently washedwith 2×50 mL of saturated aqueous brine. 34 mL of aqueous 12 N HCl (1equiv., 408 mmol) diluted in about 260 ml of DI water was added to theorganic phase. The resulting mixture was mixed (>500 rpm) for 15minutes. After settling, the aqueous layer containing thecyano(furan-2-yl)methanaminium chloride was removed and placed in aplastic holding vessel to form a stock solution. The organic layer wasthen extracted with 44 mL of DI water, followed by 46 mL of DI water.Each aqueous extract was placed in the holding vessel resulting in about460 g of aqueous phase. The aqueous phase was diluted to a total of 480grams which contained about 64.70 g (13.5 wt %) of thecyano(furan-2-yl)methanaminium chloride. 60 grams of the stock solutioncontaining about 8.1 g (51 mmol of cyano(furan-2-yl)methanaminiumchloride) was placed into a 250 mL RB flask with a stir bar. About 4.2mL (50.4 mmol) of 12N HCl and 10.4 g (101 mmol) of NaBr were added tothe flask. 30% hydrogen peroxide (20 g, 176 mmol) was added dropwiseover 50 minutes to the flask. Over a 25 min period during the addition(about 7.5 g of peroxide had been added), the reaction self heated to56° C., at which point the reaction was cooled to about 36° C. After 40minutes, solids began to form. The reaction was allowed to stir for anadditional 6 hours. The solids were collected by filtration, washed withDI water, and then dried. 6.28 grams of a free flowing, light tan powderwas obtained as a mixture of 4,6-dibromo-3-hydroxypicolinonitrile (39.1wt % yield), 6-bromo-3-hydroxypicolinonitrile (3.0 wt % yield),6-chloro-3-hydroxy-picolinonitrile (6.23 wt % yield), and one of the4/6-chloro/bromo-3-hydroxypicolinonitrile isomers (0.4 wt % yield) asdetermined by ¹H NMR. A total yield of 51% was observed. ¹H NMR (400MHz, DMSO-d₆) of the desired product: δ 8.27 (s, 1.00H), δ 8.18 (s,0.11H), δ 7.75 (d, J=8.9 Hz, 0.64H), 7.65 (d, J=8.9 Hz, 0.01H), 7.53 (d,J=8.9 Hz, 0.01H), 7.44 (d, J=8.9 Hz, 0.064H).

Example 1j. 4,6-Dibromo-3-hydroxypicolinonitrile

To a 500 mL flask outfitted with a stir bar was added 36 grams ofammonium acetate (467 mmol), 200 mL of ethyl acetate, and 7.5 grams ofNaCN (153 mmol). 75 mL of water was utilized to wash the residual sodiumcyanide into the flask and out of the funnel. Furfural (12.7 mL, 14.7grams, 153 mmol) was then quickly added to the reactor via syringe. Thetemperature in the reactor increased from about 15° C. to 24° C. Thereaction was allowed to stir overnight at ambient temperature (18° C.).The agitation was turned off to allow the two liquid phases to separate.The organic phase was then sampled for ¹H NMR analysis and the reactionwas determined to be only about 80% complete. The reaction was thenstirred at 25° C. (using a water bath) for an additional 6 hours. Thereaction was shown to be about 90% complete by ¹H NMR. 75 mL of 20%aqueous sodium carbonate was added to the reactor and allowed to stirfor 30 minutes, and then the mixture was allowed to sit without stirringfor 20-30 min. The aqueous phase was removed and then the organic phasecontaining the α-aminonitrile of furfural in ethyl acetate was washedwith 2×50 mL of saturated brine.

10 N sulfuric acid (15 mL, 1 equivalent, 153 mmol) was diluted in about225 ml of DI water. The ethyl acetate solution containing theα-aminonitrile of furfural was extracted with the diluted sulfuric acidsolution in about 1/3 portions. Each extraction was placed into a 500 mLRB with a stir bar. The organic solution was extracted with anadditional 5 mL of DI water. To the combined aqueous acid extracts wasadded 47 g of sodium bromide (459 mmol) and then hydrogen peroxide (30%,360 mmol) was added over a 2 hour period, which resulted in atemperature rise from 19° C. to about 50° C. The reaction was allowed tostir overnight. ¹H NMR analysis indicated that the reaction was a 1:1mixture of 6-bromo-3-hydroxypicolinonitrile and4,6-dibromo-3-hydroxypicolinonitrile. An additional 15 mL of 10 Nsulfuric acid and 13.5 grams of 30% peroxide (107 mmol) was added to thereaction solution and the reaction was heated to 45° C. After 2 hours,the reaction was complete as indicated by ¹H NMR analysis. The solidswere collected by filtration, washed with water, and dried to yield 21.9grams of a light tan powder. ¹H NMR analysis indicated that the powderconsisted of 4,6-dibromo-3-hydroxypicolinonitrile (49.8% yield) and6-bromo-3-hydroxypicolinonitrile (2.4% yield).

Example 1k. 3-(Acetyloxy)-4-methoxypicolinic acid

3-Hydroxy-4-methoxypicolinic acid (5.0 g, 29.6 mmol) was slurried in 50mL of pyridine and 50 mL of acetic anhydride at ambient temperature.After 1 h, a yellow solution had formed which was then stirredovernight. The solution was evaporated at 45° C. (2 mm Hg) to give 6.28g of tan solid (99% yield, mp=132-134° C.). ¹H NMR (400 MHz, DMSO-d₆) δ13.32 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 7.40 (d, J =5.5 Hz, 1H), 3.91 (s,3H), 2.27 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 167.95, 164.81, 158.34,147.87, 142.77, 136.18, 110.87, 56.59, 20.27. HRMS (m/z) calcd forC₉H₉NO₅ 211.0478, found 211.0481 ([M]⁺).

What is claimed is:
 1. A process for the preparation of a compound ofFormula A

wherein R¹ is a C₁-C₃ alkyl; from a compound of Formula B

which comprises the following steps: a) creating a first mixturecontaining an alkali metal alkoxide of Formula CMOR¹   C wherein M is Na or K, and R¹ is C₁-C₃ alkyl; and the compoundof Formula B and heating the first mixture; b) creating a second mixtureby adding water, a strong base, and zinc metal to the first mixture; c)heating the second mixture; and d) isolating the compound of Formula A.2. The process of claim 1 wherein M is Na and R¹ is methyl.
 3. Theprocess of claim 1 wherein the first mixture further comprises a solventselected from the group including DMSO, methanol, sulfolane, andmixtures thereof.
 4. The process of claim 1 wherein the strong base isselected from sodium hydroxide or potassium hydroxide.
 5. The process ofclaim 1 further including a step for removing zinc salts or zinc metalfrom the second mixture prior to heating the second mixture.
 6. Aprocess for the preparation of a compound of Formula B

from a compound of Formula D

which comprises the following steps: a) creating a first mixture bycombining together a 2-phase water-organic solvent system, an ammoniasource, a cyanide source and the compound of Formula D; b) separating asecond mixture from the first mixture containing a compound of Formula Eas a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture wherein the mineral acid is HCl, HBr, H₂SO₄, HNO₃or H₃PO₄; d) separating a fourth mixture from the third mixture that isan aqueous mixture containing a compound of Formula F;

wherein X is Cl, Br, HSO₄, NO₃ or H₂PO₄; e) adding a brominating agentincluding bromine, a bromide compound with an oxidant, and mixturesthereof to the fourth mixture to form a fifth mixture; and f) isolatingthe compound of Formula B from the fifth mixture.
 7. The process ofclaim 6 wherein the organic solvent is selected from the groupincluding, MTBE, ethyl acetate, isopropyl acetate, THF, 2-MeTHF,toluene, a xylene or a mixture of xylenes, and mixtures thereof.
 8. Theprocess of claim 6 wherein the mineral acid is hydrobromic acid.
 9. Theprocess of claim 6 wherein X is Br.
 10. The process of claim 6 whereinthe bromide compound is hydrobromic acid or a bromide salt selected fromNaBr and KBr in combination with an acid.
 11. The process of claim 6wherein the oxidant is selected from hydrogen peroxide and potassiumperoxymonosulfate.
 12. A process for the preparation of a compound ofFormula G

from a compound of Formula D

which comprises the following steps: a) creating a first mixture bycombining together a 2-phase water-organic solvent system, an ammoniasource, a cyanide source and the compound of Formula D; b) separating asecond mixture from the first mixture containing the compound of FormulaE as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture wherein the mineral acid is HCl, HBr, H₂SO₄, HNO₃or H₃PO₄; d) separating a fourth mixture from the third mixture that isan aqueous mixture containing a compound of Formula F;

wherein X is Cl, Br, HSO₄, NO₃ or H₂PO₄; e) adding a brominating agentincluding a bromide compound with an oxidant to the fourth mixture toform a fifth mixture; and f) isolating the compound of Formula G fromthe fifth mixture.
 13. The process of claim 12 wherein the organicsolvent is selected from the group including MTBE, ethyl acetate,isopropyl acetate, THF, 2-MeTHF, toluene, a xylene or a mixture ofxylenes, and mixtures thereof.
 14. The process of claim 12 wherein themineral acid is hydrobromic acid.
 15. The process of claim 12 wherein Xis Br.
 16. The process of claim 12 wherein the bromide compound ishydrobromic acid or a bromide salt selected from NaBr and KBr incombination with an acid.
 17. The process of claim 12 wherein theoxidant is selected from hydrogen peroxide and potassiumperoxymonosulfate.